CN110724144A - Pyrazolidone impurity, preparation method and application - Google Patents
Pyrazolidone impurity, preparation method and application Download PDFInfo
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Abstract
The invention discloses a mefenpyr-diethyl impurity, a preparation method and application thereof, wherein the molecular structural formula of the mefenpyr-diethyl impurity is shown as a formula I, and the preparation method takes 2, 4-dichloroaniline, nitrite and 2-ethyl chloroacetoacetate as raw materials and obtains an intermediate through diazotization and an Acupo-Clingmann reaction; then the intermediate and ethyl methacrylate are subjected to ring-closure reaction to obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, and the yield reaches more than 40 percent, and the method has the advantages of mild reaction conditions, less energy consumption, high economy and high yield; the substance has application value in the safety evaluation of the influence of the substance as an impurity on the pesticide effect of the mefenpyr-diethyl and the residue of the substance on agricultural products.
Description
Technical Field
The invention relates to the technical field of drug synthesis, and particularly relates to a mefenpyr-diethyl ester impurity, a preparation method and application thereof, wherein the chemical name of the impurity is 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate.
Background
Pyracloquintocet-mefenpyr-diethyl is a novel herbicide safener published by the Brighton plant protection conference in England 1999, is a pyrazole antidote developed by the company Amentte, and can be used together with herbicides such as mesotrione to protect wheat, barley, etc. from injury. However, some impurities are inevitably generated in the synthetic process of the mefenpyr-diethyl, the impurities not only directly concern the using effect of the mefenpyr-diethyl, but also have important influence on environmental safety and agricultural product safety, so that potential safety hazards exist to human health, and the impurities also become one of important indexes for judging the quality and the using safety of the mefenpyr-diethyl. However, since mefenpyr-diethyl has a large number of impurities and a small total content of impurities, no information on the substance has been successfully isolated and confirmed. The invention aims to provide molecular structure information, a preparation method and application of impurities with high content in mefenpyr-diethyl, wherein the chemical name of the impurities is 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and firstly provides the structural information of 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate with higher content in the impurities of the mefenpyr-diethyl; secondly, providing a preparation method of 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, wherein the preparation method has the advantages of mild reaction conditions, low energy consumption, economy and feasibility, and the yield reaches more than 40%; evaluation of the effect of triethyl-1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate as an impurity on the efficacy of mefenpyr-diethyl and evaluation of the safety of its residue on agricultural products.
An impurity of mefenpyr-diethyl, its chemical name is 1, 5-di (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, its molecular structural formula is formula I:
in order to facilitate the study of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate, a preparation method of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate is proposed, which comprises the following steps:
s1: preparing 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate, taking 2, 4-dichloroaniline, nitrite and 2-chloroacetoacetic acid ethyl ester as raw materials, and obtaining the 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate through diazotization and Yapu-Clingmann reaction, wherein the reaction formula is as follows:
s2: preparing 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, and performing cycloaddition reaction by using the 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate prepared in the step S1 and ethyl methacrylate as raw materials to obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, wherein the reaction formula is as follows:
preferably, the specific operation of step S1 is: dissolving 2, 4-dichloroaniline in a mixed solvent of ethanol and water, adding a certain amount of concentrated hydrochloric acid, controlling the temperature to be 0 ℃, and dropwise adding a nitrite water solution; then, adding 2-chloroacetoacetic acid ethyl ester, reacting for 4-5 h at 0 ℃, heating to room temperature, sequentially performing extraction, washing, drying and column chromatography on a reaction product mixed solution to obtain 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate, wherein the molar ratio of 2, 4-dichloroaniline to nitrite to 2-chloroacetoacetic acid ethyl ester to hydrogen chloride molecules added into concentrated hydrochloric acid is 1: 1.1: 1: 2.5.
Further preferably, the nitrite in step S1 is sodium nitrite or potassium nitrite.
Preferably, the step S2 further includes the following specific operations: dissolving 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate in tetrahydrofuran, adding a certain amount of p-toluenesulfonic acid, then dropwise adding ethyl methacrylate, heating to 80 ℃ after dropwise adding, reacting for 10-12H, cooling to room temperature, sequentially performing extraction, washing, concentration and column chromatography on a reaction product mixed solution to obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, wherein the mol ratio of the 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate to the p-toluenesulfonic acid to the ethyl methacrylate is 1: 1.5: 3.
In order to facilitate the crystal structure analysis of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate, a method for culturing triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate crystals, which comprises subjecting triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2 prepared in step S2, dissolving 4-triazole-3, 6,7 a-triethyl tricarboxylate in a methanol solvent, standing for 3-5 days at room temperature, and precipitating crystals.
In order to facilitate the popularization and application of the 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, the application of the 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate is proposed: the method is used for evaluating the influence of impurities on the pesticide effect of the mefenpyr-diethyl and evaluating the safety of residues of the mefenpyr-diethyl on agricultural products.
The invention has the advantages and beneficial effects that:
the invention provides structural information and a preparation method of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate with higher content in mefenpyr-diethyl impurity, wherein the preparation method comprises the following steps: 2, 4-dichloroaniline, nitrite and 2-chloroacetoacetic acid ethyl ester are used as initial raw materials, and an intermediate 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate is obtained after diazotization and Yapu-Clingmann reaction; then tetrahydrofuran is used as a solvent, the intermediate 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate and ethyl methacrylate are subjected to ring-closure reaction to obtain a reaction product mixed solution, and the reaction product mixed solution is subjected to extraction, washing, concentration, column chromatography and other treatment procedures to finally obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, wherein the yield is more than 40%; the method has the advantages of mild reaction conditions, low energy consumption, high economical efficiency and high yield; 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate is used as an impurity for evaluating the influence of the effect of the mefenpyr-diethyl and the safety of the residual on agricultural products.
Drawings
FIG. 1 is a molecular structural formula of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate in example 1;
FIG. 2 is a 1HNMR map of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate of example 1;
FIG. 3 is an MS spectrum of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate of example 1;
FIG. 4 is a high performance liquid chromatogram of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate of example 1;
FIG. 5 is a crystal structure diagram of triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate in example 1.
Detailed Description
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
The preparation method of the invention is used for preparing 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, and comprises the following steps:
s1: a250 mL three-necked flask was charged with 2, 4-dichloroaniline (10.2g,63.4mmol), ethanol (20mL), water (7mL) and concentrated hydrochloric acid (13mL) at controlled temperatureDropwise adding sodium nitrite aqueous solution (NaNO) into the three-neck flask at 0 ℃ under the stirring state2: 4.69g,69.7mmol；H215mL), continuously reacting for 30 minutes after dropwise addition, adding ethyl 2-chloroacetoacetate (10.88g,63.4mmol), sodium acetate (15.6g, 190.1mmol) and water (90mL) into a three-neck flask, continuously stirring and reacting for 4-5 hours at the temperature of 0 ℃, detecting the reaction process by Thin Layer Chromatography (TLC), wherein a developing agent used by the TLC is a mixed solution of petroleum ether and ethyl acetate (the volume ratio of the petroleum ether to the ethyl acetate is 5:1), heating to room temperature after the reaction is finished, and sequentially extracting, washing, drying and purifying by column Chromatography to obtain an intermediate 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate (14.3g), wherein the yield of the intermediate is 76%.
S2: dissolving 2-chloro-2- (2, 4-dichlorophenyl) -ethyl glyoxylate (5.9g,0.02mol) in THF (50mL), adding p-toluenesulfonic acid (5.2g, 0.03mol) under the condition of stirring at room temperature, then adding ethyl methacrylate (6.8g,0.06mol) dropwise, heating to 80 ℃ after the dropwise addition, stirring and reacting for 12 hours at 80 ℃, detecting the reaction process by TLC, wherein a developing agent used by TLC is a mixed solution of petroleum ether and ethyl acetate (the volume ratio of the petroleum ether to the ethyl acetate is 3:1), cooling to room temperature after the reaction is finished, and sequentially extracting, washing, drying and purifying a mixed solution by column chromatography to obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate as a white solid (5.3g) in 42% yield and 99.8% purity.
S3: dissolving the triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate (100mg) prepared in the step S2 in 5mL of methanol solvent, standing for 3-5 days at room temperature, and naturally volatilizing the solvent to precipitate crystals.
The molecular structural formula of the 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate is shown in figure 1;
NMR analysis of the triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate white solid prepared in step S2 was carried out by BUUKER AV-400 NMR, the results are shown in FIG. 2;
mass spectrometry was performed on the triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate white solid prepared in step S2 using a Thermo LTQ-orbitrap XL mass spectrometer, and the results are shown in FIG. 3;
the purity of the triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate white solid prepared in the step S2 was analyzed by HPLC, and the result is shown in FIG. 4;
subjecting the 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] cultured in step S3 to a Bruker Smart Apex CCD single crystal diffractometer]The structure analysis is carried out on the-1, 2, 4-triazole-3, 6,7 a-triethyl tricarboxylate monocrystal, colorless crystals with the size of 0.11mm multiplied by 0.15mm multiplied by 0.9mm are selected for carrying out the crystal structure determination, a Bruker SmartApex CCD monocrystal diffractometer is adopted, and MoK monochromatized by a graphite monochromator is usedαThe diffraction numbers were collected in phi-omega scans using radiation (lambda: 0.71073nm) and the results are shown in figure 5.
FIG. 2 shows nuclear magnetic hydrogen spectrum data of1H-NMR: delta ppm 7.729 to 7.734(d,1H), 7.516 to 7.544(m,2H),7.402 to 7.448(m,2H),7.335 to 7.357(d,1H), 4.260 to 4.400(m,2H),4.096to 4.148(m,2H),3.960 to 3.997(d,1H), 3.684 to 3.762(m,2H),3.652 to 3.689(d,1H),1.205 to 1.240(t,3H), 0.952 to 0.987(t,3H),0.830 to 0.865(t,3H), and 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ]]-1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate molecular formula C26H26Cl4N4O6The peak positions of the medium hydrogen atoms are consistent;
FIG. 3 Mass Spectrometry data show the results [ M + H ] using a mass spectrometer (Thermo LTQ-orbitrap XL), solvent methanol, Positivepolarity ESI (+)/ESI, Mass Spectrometry ESI (+)]+ has an M/z of 631.2, [ (M-CH)3CH2O+H)+H]+M/z of 587.1, [ (M-CH)3CH2O+H-CH3CH2+H)+H]+M/z of 559.0, the molecular weight of the sample can be presumed to be 630.1, and C26H26Cl4N4O6The theoretical molecular weight is consistent;
FIG. 4, liquid chromatogram showing: the normalized content of the product is 99.8 percent, and the purity is higher;
FIG. 5 shows the crystal structure of the compound obtained by SHELXTL mapping software, and it can be seen from the crystal structure diagram of FIG. 5 that the crystal structure is consistent with the molecular structure of the triethyl 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-tricarboxylate compound.
In order to facilitate the popularization and application of the 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, the application of the 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate is proposed: the method is used for evaluating the influence of impurities on the pesticide effect of the mefenpyr-diethyl and evaluating the safety of residues of the mefenpyr-diethyl on agricultural products.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. The mefenpyr-diethyl impurity is characterized in that the chemical name of the mefenpyr-diethyl impurity is 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, and the molecular structural formula of the mefenpyr-diethyl impurity is shown as a formula I:
2. a preparation method of mefenpyr-diethyl impurity is characterized by comprising the following steps:
s1: preparing 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate, taking 2, 4-dichloroaniline, nitrite and 2-chloroacetoacetic acid ethyl ester as raw materials, and obtaining the 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate through diazotization and Yapu-Clingmann reaction, wherein the reaction formula is as follows:
s2: preparing 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, and performing cycloaddition reaction by using the 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate prepared in the step S1 and ethyl methacrylate as raw materials to obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, wherein the reaction formula is as follows:
3. the method for preparing mefenpyr diethyl impurity as claimed in claim 2, wherein the step S1 comprises the following specific operations: dissolving 2, 4-dichloroaniline in a mixed solvent of ethanol and water, adding a certain amount of concentrated hydrochloric acid, controlling the temperature to be 0 ℃, and dropwise adding a nitrite water solution; then, adding 2-chloroacetoacetic acid ethyl ester, reacting for 4-5 h at 0 ℃, heating to room temperature, sequentially performing extraction, washing, drying and column chromatography on a reaction product mixed solution to obtain 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate, wherein the molar ratio of 2, 4-dichloroaniline to nitrite to 2-chloroacetoacetic acid ethyl ester to hydrogen chloride molecules added into concentrated hydrochloric acid is 1: 1.1: 1: 2.5.
4. The method according to claim 3, wherein the nitrite in step S1 is sodium nitrite or potassium nitrite.
5. The method for preparing mefenpyr diethyl impurity as claimed in claim 4, wherein the specific operation of the step S2 is as follows: dissolving 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate in tetrahydrofuran, adding a certain amount of p-toluenesulfonic acid, then dropwise adding ethyl methacrylate, heating to 80 ℃ after dropwise adding, reacting for 10-12H, cooling to room temperature, sequentially performing extraction, washing, concentration and column chromatography on a reaction product mixed solution to obtain 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate, wherein the mol ratio of the 2-chloro-2- (2, 4-dichlorophenylhydrazone) -ethyl glyoxylate to the p-toluenesulfonic acid to the ethyl methacrylate is 1: 1.5: 3.
6. Use of the mefenpyr-diethyl impurity as claimed in claim 1, wherein the effect of 1, 5-bis (2, 4-dichlorophenyl) -6-methyl-1H, 5H-pyrazolo [5,1-c ] -1,2, 4-triazole-3, 6,7 a-triethyl tricarboxylate as an impurity on the efficacy of mefenpyr-diethyl and the safety assessment of its residual on agricultural products are assessed.
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